ABSTRACT ? PROJECT 1 Recent advances in human genetics and genomics provide novel opportunities for the identification and validation of drug targets. Aging is a major risk factor for many chronic diseases, including cardiovascular disease, neurodegenerative diseases and a wide range of cancers. Interventions targeting the underlying process of aging are expected to provide significant benefits to human health and substantially reduce the social and economic costs associated with age-related disease and frailty. Studies in model organisms have demonstrated that the rate of aging and the frequency and severity of age-related pathologies are influenced by conserved genetic pathways and factors. Furthermore, genetic or pharmacological manipulation of these conserved aging pathways can dramatically extend lifespan and healthspan in laboratory animals. This overwhelming evidence raises hopes for new drugs that slow the aging process and attenuate age-related disease in humans by modulating the conserved pathways of aging. The experiments outlined in this proposal are aimed at exactly this goal by translating the breakthrough discoveries made in the model organisms into the human situation. Genetic and epigenetic variants associated with longevity are potential targets for therapeutic modulation and can provide strong support for their therapeutic validity as a drug target against multiple age-related disease rather than a single disease at once. Here, we propose to identify and functionally characterize genetic and epigenetic variants, the latter in the form of inter-individual variation in miRNA expression levels, associated with human healthy aging and extreme longevity for therapeutic modulation to improve human health span and lifespan. The information generated in Project 1 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.